Abnormalities in neurotransmitter systems have frequently been
recorded in autism. Clinical observations include both elevated
and lowered levels of various neurotransmitters compared to controls,
including alterations in monoamine metabolism [3654486,
2653386,
3215884],
neurotransmitter peptides [9018016,
9315980],
with considerably raised levels of beta-endorphin (for vasopressin/oxytocin
see Hormones) and altered activities
of cholinergic receptors, with binding of muscarinic M(1) receptor
being up to 30% and that of nicotinic receptors being 65%-73%
lower in the autistic group compared to controls [11431227].
Postmortem brain examination noted abnormalities of the glutamate
neurotransmitter system in autism, with specific abnormalities
in the AMPA-type glutamate receptors and glutamate transporters
in the cerebellum [11706102].
Expression of several types of GABA receptors is altered in brains
of subjects with autism, with levels being significantly reduced
in autism compared to controls [18821008,
19002745].

Dysregulations of serotonergic systems in particular have been
documented, such as abnormalities in brain serotonin sythesis,
with significant reductions in synthesis capacity compared to
controls [10072042,
9382481],
while at the same time plasma levels of serotonin and free thryptophan
appear to be on average 30-50% percent higher in individuals with
autism [6204248].
Autoantibodies to serotonin receptors [9067002]
and reduced receptor binding have also been recorded [16648340].
Of note is that one study found correlation of elevated plasma
serotonin levels and the the major histocompatibility complex
(MHC) types associated with autism [8904735].

Calcium influx through VGCCs is a key step in secretion
of neurotransmitters, for example serotonin [16047543].
Due to vesicle priming in neuronal excytosis, the influx of calcium
ions is all that is needed to trigger nearly instantaneous neurotransmitter
release in neurons [12043844].
Moreover, some findings indicate that its excessive entry through
LTCC during early development may to alter neuronal response properties
at later ages [9437025].
Especially in developing brain modulation of neurotransmitter
release by dihydropyridine-sensitive calcium channels involves
tyrosine phosphorylation. As the neurons develop
a network of neurites, both tyrosine phosphorylation and LTCC
activity seem to decrease [9987031,
11226706]
(see Brain). This transmitter-secretion
effect of LTCC is G-protein-linked and sensitive to pertussis
toxin treatment [8994064].
Influx of calcium through N-type VGCC directly stimulates dopamine
release and this effect can be attenuated by chalcium channels
blockers [11769325,
15272204].
The involvement of LTCC-linked IP3-sensitive intercellular stores
in the calcium-triggered release of dopamine and acetylcholine
has also been observed [14657041].
Secretion of beta-endorphin, whose levels are significantly elevated
in autism, is also triggered by calcium influx into the cell and
can be lowered in vitro by applying calcium channel blockers [2428932,
10371405].

Following the findings of significant modifications of catecholamine
metabolites in autism it may be worth mentioning that the activities
of Catechol-O-methyl transferase (COMT), an enzyme involved in
the breakdown of the catecholamine neurotransmitters, are inhibited
by raised calcium levels in tissue [12170607].
Additionally, a small pilot study examining administration of
tetrahydrobiopterin (R-BH4), a cofactor for tyrosine hydroxylases
in the pathway of catecholamines and serotonin, reported amelioration
of several autistic traits in study subjects. Decreased dopamine
D2 receptor binding was also reported (see below) [9236697].
Tyrosine hydroxylase (TH) is an enzyme of central
importance in catecholamine biosynthesis and the expression level
of its gene is controlled by several calcium signalling pathways,
most importantly LTCC-regulated CREB (see Brain)
[15001085,
9645965].
In so called Tottering mice, an animal model with inherited mutation
in calcium channels, the increased density of LTCC in the brain
is followed by abnormal regulation of tyrosine hydroxylase. In
vivo chronic nimodipine treatment was shown to significantly reduce
the expression of TH mRNA in these mice [14715436].

In vivo application of calcium channel agonist and antagonists
points to a possible role played by calcium inward currents in
synthesis and metabolism of dopamine and serotonin in
brain, with different effect observed in specific areas
of rodent brain [7683338,
2431107,
7545305]

Abnormal stimulation of dopamine or serotonin
receptors have been hypotesised as able to lead to the
types of neuroanatomical changes observed in autism, schizophrenia
and bipolar disorder. Of relevance is the close interplay and
interdependence of dopamine receptors and VGCCs, especially the
effect of D1 receptor activation on LTCC function and CREB-influenced
gene expression. It has been observed that activation of dopamine
D1 receptors alters the properties of LTCC blockers and turns
them into facilitators of calcium influx. In other words in D1
receptor-stimulated neurons these agents, instead of blocking
calcium, actually promote its entry, which leads to the activation
of signalling pathways and CREB phosphorylation. [15530653,
14622123].
(see Brain). These same mechanisms
have been observed in the effects of psychostimulants on gene
expression [16724157].

In addition, D2 and D4 dopamine receptors, together with muscarinic
receptors (especially M1), are also able to modulate one of the
subtypes of LTCC. These effects are likely controlled by pertussis
toxin sensitive G-proteins and linked to postsynaptic density
proteins, notably Shank [15689540,
12496094,
7477916,
10437116,
9000430,
15615835].

Of possible relevance in this context is also the involvement
and influence of opiod receptors on these mechanisms, and the
observation that Naltrexone is able to modulate the functioning
of D2 receptors, in a dose dependent manner (see Other_Receptors
and Current_Therapies).

Brain serotonin level is suspected to play an
important role in developing brain and impairments of serotonin
metabolism have been implicated in autism. Maternal serotonin
levels have been suggested as being of central importance for
develping fetal brain (see Maternal).
Reduced brain levels of tryptophan and/or serotonin in the brain
and its receptors have been recorded in some viral infections
(see Viruses). Several
in vitro studies have noted the inhibitory effects of serotonin
and its receptors on the function of VGCC and neuronal migration
during development [11976386,
11494406,
12401168].
Calcium influx through LTCC may play an important role in the
regulation of the serotonine 5-HT2A receptor expression levels
and function [11474845].
Another pathway that influences the expression of these receptors
is linked to activation of PKC [9928249,
11299321].
It has been observed that activities and expression of 5-HT2A
and several other serotonin receptors are also tightly linked
to the levels of cholesterol as well as caveolin Cav-1 (see Membranes
and Smith-Lemli-Opitz Syndrome) [17064686,
15157621,
15190056].
Levels of membrane cholesterol have also been suggested to play
a role in activities of serotonin transporter (SERT), responsible
for the reuptake of serotonin [11523992].

Relative to expression and function of nicotinic receptors
in autism, significantly lowered binding of some agonists to nicotinic
receptors has been observed. For example binding of the agonist
epibatidine in cortical areas to was up to 73% lower in autism
group compared to controls. As with serotonine receptors, some
of the nicotinic receptors have been noted to be significantly
permeable to calcium and so able to regulate several neuronal
processes. This mechanism is linked to activation and function
of both LTCC and intracellular calcium receptors [11157063,
12065669,
11498514].
On the other hand, there is now ample evidence that altering calcium
dynamics can modulate neuronal nAChR function [7542542,
9415721,
12915265].
Of interest are the preliminary reports of therapeutic action
of galantamine in autism [15152789,
17069550],
considering that neuroprotective actions of galantamine are thought
to be linked to its modulation of nicotinic receptors [12649296].

A postmortem study revealed greatly reduced levels of glutamic
acid decarboxylase (GAD) 65 and 67 kDa proteins in several
areas of the brains of individuals with autism [12372652].This
was confirmed by more recent results that showing GAD67 mRNA level
reduced by 40% in the autistic group when compared to controls
[17235515].
Another study found serum levels of glutamate in the patients
with autism were significantly higher than those of normal controls
[16863675].
Gamma-aminobutyric acid GABA is the chief inhibitory neurotransmitter
in the central nervous system. Glutamic acid decarboxylase (GAD)
is the enzyme responsible for conversion of excitatory neurotransmitter
glutamate to GABA in the brain, and its activity is regulated
by calcium homoestasis - it has been demonstrated that the activity
of GAD depends on the strict balance of extracellular and intracellular
levels of calcium, as well as between the free and stored calcium
in the cell [6856025,
12603819,
10366697,
12603819].
In addition, the expression levels of mRNA of genes encoding for
GAD and GABA appear to be regulated by calcium transients in developing
neurons [11085875,
16154277]
(also see Brain)

Also worth noting is that glutamate has been implicated in epileptic
seizures: “Microinjection of glutamic acid into neurons
produces spontaneous depolarisations … and this firing pattern
is similar to what is known as paroxysmal depolarising shift in
epileptic attacks. This change in the resting membrane potential
at seizure foci could cause spontaneous opening of voltage activated
calcium channels, leading to glutamic acid release and further
depolarization…”. There is growing evidence that
apart from NMDA receptors, LTCC also play a role in glutamate
excitotoxicity [10493768].

In rat dopaminergic neurons secretion of excitatory amino acids
aspartate and glutamate was found to be directly regulated by
activities of L-type calcium channels, and it was suggested by
the authors that the drugs that modulate presynaptic LTCC may
show to be of use in neurological and psychiatric disorders that
involve the dopamine system [9712641].

The coupling of cholinergic, dopamine and serotonine receptors
to calcium channels and their sensitivity to cellular calcium
dynamics is proposed to be one of the reasons for the observed
abnormalities of these systems in autism. Disturbed calcium homeostasis
could also be one likely mechanims behind the abnormal secretion
rhythms of various neurotransmitters as well as the lowered activities
of GAD and abnormal levels of glutamate in autism.